Cellular growth, function, differentiation and development are regulated by a variety of different mechanisms. Among the most important regulators of cells are the receptor-specific proteins called "cytokines". These proteins bind to specific membrane-associated receptors which, in turn, transduce intracellular signals that ulitmately regulate the expression of critical genes and thereby control many cellular functions.
Interleukin-6 ("IL-6") is one of the most well characterized and studied cytokines. It functions through the interaction with at least two transmembrane glyprotein receptor molecules on the surface of target cells (Taga, et al., J. Exp. Med. 166: 967-981 (1987); the interleukin-6 receptor ("IL-6R") and the signal transducer, gp130 (Yamasaki, et al., Science 241: 825-828 (1988); and Hibi et al., Cell 63: 1149-1157 (1990)). Signal transduction by IL-6 involves the concerted action of both IL-6R and gp130. Initially, IL-6 binds to IL-6R with low affinity (Taga et al., Cell 58: 573-581 (1989)). This initial binding event induces the formation of a ternary complex consisting of two molecules of gp130 dimerized with two IL-6/IL-6R ligand-receptor complexes. In this ternary complex, IL-6 is bound with high affinity resulting in the transduction of intracellular signals by the gp130 molecules (Ward et al., J. Biol. Chem. 269: 23286-23289 (1994)).
In addition to playing an important role in modulating normal cellular function, IL-6 overproduction has been implicated in many different disease states. Recently, many investigators have focused on the suppression of IL-6 production, function and/or signal transduction as potentially useful means of inhibiting the cellular proliferation which is associated with different disease states. Vink, et al. (J. Exp. Med. 1: 997-1000(1990)) describe the inhibition of plasmacytoma growth in vivo by using antibodies directed against IL-6 or its receptor component, IL-6R. More recently, antisense oligonucleotides have been studied for use as inhibitors of cellular proliferation. Levy et al. (J Clin. Invest. 88: 696-699 (1991)) describe the use of antisense oligonucleotides which are complementary to the mRNA encoding the IL-6 protein. Fujita (PCT Application No. WO 94/25036) describes the use of antisense oligonucleotides which are complementary to the initiator codon of the mRNA encoding IL-6R.
The field of "antisense therapeutics" refers to the use of oligonucleotides which are complementary to target nucleic acids, most usually mRNA, as regulators of nucleic acid function. An antisense oligonucleotide, i.e. an oligonucleotide having a nucleic acid sequence which is complementary to that of the "sense" nucleic acid to which it is targeted, can function in many different ways to modulate nucleic acid function. When the targeted nucleic acid is MRNA, it may function by preventing translation of the MRNA into protein or inhibiting the binding or translocation of ribosomes. When the targeted nucleic acid is DNA, it may prevent transcription into mRNA.
In addition to inhibiting the production and/or function of MRNA by a "sequence specific" antisense mechanism, the effect of certain oligonucleotides, and particularly phosphorothioate oligonucleotides, can be partially attributed to non-sequence specific mechanisms. Such mechanisms have been reported to account for some of the effects of phosphorothioate oligonucleotides as anti-viral agents. (Stein, et al., Pharmac. Ther. 52: 365-384 (1991); Majumdar, et al., Biochemistry 28: 1340 (1989)).
It is an object of the present invention to provide oligonucleotides which effectively inhibit disease-associated cellular proliferation and/or growth. Such oligonucleotides are complementary to the mRNA encoding the IL-6R, and function via sequence specific and/or non-sequence specific mechanisms. A further objective of the present invention is to provide pharmaceutical compositions suitable for administration to human subjects comprising these oligonucleotides.